Given the tremendous advances of pharmaceutical innovations in the area of drug development and discovery, the advancement of pharmaceutical manufacturing science has lagged in comparison. While the cost of drug discovery dominates the overall spending in pharmaceutical research, the cost of process development and manufacturing has reached an all-time high, consequently garnering both regulatory and industrial support for a shift from batch to continuous manufacturing. The advantages for continuous manufacturing include improved process integration, smaller equipment and facilities, and real-time process monitoring and control. These engineering improvements may lead to regulatory and economic benefits such as better and more consistent product quality, lower capital and operating cost, and increased safety, which then translate to more affordable and efficacious drug products. As in any chemical processes, the successful implementation of a continuous process is largely dependent on its design, scalability and robustness.
Plug-flow crystallization (PFC) has shown considerable promise in these regards due to its fast start-up dynamics, excellent mixing, and flexible temperature and (anti-)solvent control when compared with other types of continuous crystallizers, such as mixed-product mixed suspension reactors (MSPR). In addition, more advanced control of crystal quality using plug-flow crystallization has recently been demonstrated.
Nevertheless, plug-flow crystallization is plagued with fouling or encrustation, which prevents it from being the ideal continuous crystallizer. Encrustation is a phenomena by which uncontrolled crystallization takes place at the reactor surface, resulting in a number of operational issues, such as flow blockage, reduced heat transfer due to increased thermal resistance, and reduced supersaturation. These events result in limited continuous operation and reduced crystal quality and yield.